CN112457171B - Synthetic method of hydroxytyrosol - Google Patents

Synthetic method of hydroxytyrosol Download PDF

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CN112457171B
CN112457171B CN202011474334.4A CN202011474334A CN112457171B CN 112457171 B CN112457171 B CN 112457171B CN 202011474334 A CN202011474334 A CN 202011474334A CN 112457171 B CN112457171 B CN 112457171B
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hydroxyphenylethanol
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copper
bromo
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杨超文
王蕾
宋家良
关志帅
符定良
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Shenzhen Dieckmann Technology Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/02—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of halogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
    • B01J31/2234—Beta-dicarbonyl ligands, e.g. acetylacetonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4288—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using O nucleophiles, e.g. alcohols, carboxylates, esters
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Abstract

The invention belongs to the field of organic synthesis, and discloses a synthetic method of hydroxytyrosol, which comprises the following steps: reacting 3-bromo-4-hydroxyphenylethanol with an alkali metal hydroxide and a copper catalyst, wherein the copper catalyst is at least one of 8-hydroxyquinoline copper, copper acetylacetonate and BFMO-cuprous iodide. The process route of the invention has no hydroxyl protection and deprotection steps, does not need to replace bromine with methoxy, realizes hydroxyl substitution in aqueous solution of sodium hydroxide under the catalysis of copper catalyst, has good selectivity and short reaction route, can obtain the product by only two steps, and solves the problem of overlong existing process route.

Description

Synthetic method of hydroxytyrosol
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of hydroxytyrosol.
Background
Hydroxytyrosol, also known as hydroxytyrosol, 2- (3, 4-dihydroxyphenyl) -ethanol, 3, 4-dihydroxyphenylethanol, 4- (2-hydroxyethyl) -1, 2-benzenediol. Hydroxytyrosol is extracted and separated from olive oil with the reputation of 'liquid platinum', 'Mediterranean nectar' and the like, and is mainly distributed in olive fruits and olive leaves in nature, but many plants discovered at present also contain the hydroxytyrosol components, and for example, lilac leaves, clove leaves in koreanum and the like all contain the effective components of the hydroxytyrosol. Two hydroxyl groups are connected to a benzene ring of hydroxytyrosol, which is a main antioxidant active group, and the multiple biological effects of the hydroxytyrosol are mostly related to the antioxidant property of the hydroxytyrosol as polyphenol. Research shows that the hydroxytyrosol has strong antioxidation, and is beneficial to keeping bone mineral density and preventing osteoporosis; has anticancer effect; the harm of smoking to human bodies can be effectively reduced; has antibacterial effect; is helpful for treating diseases related to mitochondrial dysfunction such as diabetes and obesity, and can reduce incidence of the diseases. The product has good application prospect as food additive, cosmetic and health product.
The prior art has the following synthetic methods:
the method comprises the following steps: takes pyrocatechol and glyoxylic acid as raw materialsTo obtain 3, 4-dihydroxy mandelic acid, removing alpha-hydroxy of 3, 4-dihydroxy mandelic acid with sodium bisulfite or sodium metabisulfite as reducing agent, esterifying, reducing, and reacting in four steps to synthesize hydroxytyrosol with total yield of 52.7%. The method has cheap raw materials, long route, regioselective by-products in Friedel-crafts reaction, unfavorable purification and the use of LiAlH4Reduction is expensive, potential safety hazards exist, and the total yield is low.
Figure BDA0002834613070000011
The second method comprises the following steps: the hydroxytyrosol is synthesized by taking the p-hydroxyphenylethanol as a raw material through five steps of bromination, methoxylation, ester formation protection, reduction and hydrochloric acid hydrolysis, the yield is 46.9 percent, the method has a long route, boron tribromide is used, the problems of safety and environmental pollution exist, the total yield is low, and the cost is high.
Figure BDA0002834613070000021
The third method comprises the following steps: catechol is used as an initial raw material, hydroxyl of the catechol is protected and brominated to prepare 3, 4-methylenedioxybromobenzene, a Grignard reagent is prepared, the Grignard reagent reacts with ethylene oxide, and finally the protecting group is removed, so that the high-purity hydroxytyrosol is obtained with the total yield of 24 percent in 5 steps. The method has long synthesis steps, uses bromine and boron tribromide with serious environmental pollution, relates to the Grignard reaction with harsh conditions, and has low total yield.
Figure BDA0002834613070000022
The method four comprises the following steps: 3, 4-dimethoxy phenylacetic acid is used as a starting material to prepare 3, 4-dihydroxy phenylacetic acid, and then SOCl is added2Methyl 3, 4-dihydroxybenzoate was obtained by reaction with methanol in the presence of methanol, and methyl 3, 4-dihydroxybenzoate was reduced with sodium/ethanol to obtain hydroxytyrosol in a total yield of 41% in accordance with the Bouvault-Blanc reaction. The method has high cost of raw materials, and uses ringHydrobromic acid with serious environmental pollution and sodium reduction with potential safety hazard, and the total yield is low.
Figure BDA0002834613070000023
In a word, the existing synthesis route is long, the yield is low, the cost is high, and the used reagents thionyl chloride, bromine and boron tribromide are not environment-friendly and unsafe, have large environmental destruction and high requirements on equipment, and the aluminum lithium hydrogen is an expensive and unsafe reagent in the industry. Because the hydroxytyrosol is viscous oily liquid, the solvent residue is difficult to remove, the common distillation method is inconsistent with the stability of the hydroxytyrosol, and the cost is too high by completely depending on column chromatography. Thus, none of the existing methods provide a good purification scheme for hydroxytyrosol.
In view of the important biological activity and market demand of hydroxytyrosol, a novel hydroxytyrosol preparation process with low cost and simple operation needs to be developed in order to overcome the defects of the existing process.
Disclosure of Invention
The invention aims to provide a method for synthesizing hydroxytyrosol, which has high yield, simple and convenient post-treatment and economic steps.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method of synthesizing hydroxytyrosol, which comprises the steps of b: reacting 3-bromo-4-hydroxyphenylethanol with an alkali metal hydroxide and a copper catalyst, wherein the copper catalyst is at least one of 8-hydroxyquinoline copper, copper acetylacetonate and BFMO-cuprous iodide,
Figure BDA0002834613070000031
the BFMO ligand has the structure
Figure BDA0002834613070000032
Further, the alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide, and the copper catalyst is 8-hydroxyquinoline copper.
Further, the molar ratio of the 3-bromo-4-hydroxyphenylethanol to the alkali metal hydroxide is 1: 3 to 8.
Further, the molar ratio of the 3-bromo-4-hydroxyphenylethanol to the alkali metal hydroxide is 1: 5.
furthermore, the dosage of the copper catalyst is within 10 mol% of the 3-bromo-4-hydroxyphenylethanol.
Furthermore, the dosage of the copper catalyst is 5-10 mol% of the 3-bromo-4-hydroxyphenylethanol, namely when the dosage of the 3-bromo-4-hydroxyphenylethanol is 1mol, the dosage of the copper catalyst is 0.05-0.1 mol.
Further, the solvent of step b is water.
Further, the reaction temperature in the step b is 80-110 ℃.
Further, the reaction temperature of the step b is 95 ℃.
Further, the step b is as follows: dissolving 3-bromo-4-hydroxyphenylethanol, alkali metal hydroxide and a copper catalyst in a solvent, after the reaction is finished at the reaction temperature, cooling to the normal temperature, dropwise adding hydrochloric acid to adjust the pH to be below 2, filtering by using kieselguhr, adding saturated salt water into mother liquor, extracting by using an organic solvent, drying, concentrating the solvent, and distilling under reduced pressure by using a molecular evaporator to obtain a product.
Hydroxytyrosol is easily soluble in water, but at a very low pH, it can be extracted with a specific organic solvent after adding a saturated aqueous solution of sodium chloride.
When the molecular evaporator is used for reduced pressure distillation, materials are added from the upper opening, flow downwards along the wall of the instrument according to gravity, and flow downwards while forming a film on the wall of the instrument through the scraper, so that a product can be obtained under the condition that the temperature is much lower than that of the conventional reduced pressure distillation, and the product deterioration caused by high temperature required by the conventional reduced pressure distillation is avoided. The distillation time is also very short, since the wall path for the product to flow down is very short and the flow is evaporated to the end. By controlling the sample introduction speed and the sample introduction amount, continuous sample introduction and continuous discharge are realized, the time for contacting the product with high temperature is short, the product is evaporated in a short time, deterioration is avoided, and large-scale production can be realized under the condition of ensuring the quality.
Further, the organic solvent for extraction is tetrahydrofuran, butanol or tert-butanol.
Further, hydrochloric acid is used to adjust the pH to 1 in step b.
Further, before adding saturated brine to the mother liquor, dichloromethane was added to the mother liquor to extract impurities.
Further, the step a is performed before the step b: reacting 4-hydroxyphenylethanol with potassium monopersulfate composite salt and bromine salt to prepare 3-bromo-4-hydroxyphenylethanol,
Figure BDA0002834613070000041
further, the bromine salt is sodium bromide or potassium bromide.
Further, the molar ratio of the 4-hydroxyphenylethanol to the potassium monopersulfate complex salt to the bromine salt is 1: 0.5-3: 1 to 3.
Further, the molar ratio of the 4-hydroxyphenylethanol to the potassium monopersulfate complex salt to the bromine salt is 1: 0.8: 1.
the potassium monopersulfate compound salt is a compound salt of potassium monopersulfate, potassium bisulfate and potassium sulfate, and has a structural formula of 2KHSO5·KHSO4·K2SO4。
Further, the solvent of the step a is a mixed solvent of water and acetone.
Further, the reaction temperature in the step a is below 25 ℃.
Further, the reaction temperature of the step a is 0-25 ℃.
Further, the step a is as follows: dissolving 4-hydroxyphenylethanol in a solvent, adding potassium monopersulfate composite salt at a reaction temperature, then adding an aqueous solution of a bromine salt, adding a reducing agent after the reaction is finished to quench the reaction, decompressing and evaporating the solvent, filtering, washing and drying to obtain the product.
Further, the reducing agent is sodium thiosulfate or sodium bisulfite.
The invention has the following beneficial effects:
1. the process route of the invention has no hydroxyl protection and deprotection steps, does not need to replace bromine with methoxy, realizes hydroxyl substitution in aqueous solution of sodium hydroxide under the catalysis of copper catalyst, has good selectivity and short reaction route, can obtain the product by only two steps, and solves the problem of overlong existing process route.
2. The reagents used in the invention are mostly inorganic salts, and are cheap and environment-friendly. Reagents such as thionyl chloride, bromine, boron tribromide and the like which are not environment-friendly, unsafe and have large corrosivity on equipment are avoided; the aluminum lithium hydrogen is avoided being used as a reducing agent, so that the potential safety hazard of production is reduced, and the cost is reduced; the catalytic coupling reaction is realized by using copper to replace noble metal, the copper and the ligand are cheap and easy to obtain, and the preparation is simple.
3. When the optimal copper catalyst is selected, the total yield can reach 70%, the product purity is high (more than 99%), wherein the copper catalytic coupling reaction is carried out under the condition of relatively low concentration of reaction liquid, the oxidation speed of hydroxytyrosol can be reduced and controlled, and the yield is more than 80%.
4. The method has the advantages of simple operation, simple and convenient post-treatment, no need of steps such as silica gel column chromatography and the like, low requirements on production conditions and equipment, no toxicity and harmlessness of the used solvent, reduction of the using amount of the organic solvent especially when the step b is carried out in water, environmental protection, and solution of the problems of complex preparation conditions, difficult control, high equipment requirements, high raw material price and the like of the hydroxytyrosol.
5. The invention thoroughly solves the problem of solvent residue of the hydroxytyrosol and the problem of stability of the hydroxytyrosol caused by thermal sensitivity by a molecular distillation method, is safe and efficient, and is easy for industrial production.
6. In the process production, the typical introduction method of the phenol hydroxyl group is to take halogenated benzene as a substrate, introduce methoxyl group by reacting with methanol, and then demethylate under strong acidity. And little consideration has been given to the one-step construction of phenolic hydroxyl groups by direct aqueous phase reaction under copper catalysis. For copper-catalyzed ullmann coupling reaction, a halogenated benzene ring with an electron-withdrawing group is often used as a substrate, and a substitution reagent is mainly organic alcohol, organic amine or formed active carbon anions. And the Ullmann coupling reaction with an electron-donating group is not beneficial to the implementation of substitution reaction from the viewpoint of electronic effect, and usually solvents with high boiling points such as DMSO (dimethyl sulfoxide) are needed, so that the environment is not protected, the resource is not saved, and meanwhile, the purification of hydroxytyrosol is seriously interfered by the high boiling point of DMSO. The substrate in the step b of the invention is provided with electron donating groups, an effective copper catalyst is screened out, the use of an organic solvent is avoided, the hydroxyl leading participation effect is utilized, the hydroxyl substitution reaction is successfully realized in the water phase at the reflux temperature, and the decomposition of hydroxytyrosol caused by high temperature is avoided.
Detailed Description
The present invention will be further described with reference to the following specific examples. The following parts are all parts by weight.
Example 1
1. Preparation of 3-bromo-4-hydroxyphenylethanol
Figure BDA0002834613070000051
69.1g (0.5mol) of 4-hydroxyphenylethanol, 500mL of water and 200mL of acetone are added to a three-necked flask. The mixture is put into an ice water bath, the temperature is reduced to below 15 ℃, and 250g (0.407mol) of potassium monopersulfate complex salt is added in batches. A50 wt% aqueous solution of sodium bromide (containing 51.5g of sodium bromide, 0.5mol) prepared in advance was slowly added dropwise thereto, and the temperature was controlled to 20 ℃ or lower. After the addition was complete, the reaction was continued for an additional 1 hour in an ice-water bath. TLC analysis (developing agent PE: EA is 2: 1), after the reaction is finished, sodium thiosulfate 39.5g (0.25mol) is slowly added in batches in an ice-water bath to quench the reaction, after the dropwise addition is finished, the reaction solution is poured into a single-neck bottle, acetone is evaporated under reduced pressure below 45 ℃, crystals are separated out, the crystals are filtered, washed by water and dried in an air-blast drying oven, and 99.3g (0.4576mol) of the product is obtained, wherein the molar yield is 91.52%.
Characterization data:
1HNMR(400MHz,MeOD):δ7.32(s,1H),6.99-7.01(d,1H),6.80-6.82(d,1H),4.91(s,2H),3.67-3.71(t,2H),2.67-2.71(t,2H)；13CNMR(400MHz,MeOD):156.12,136.94,135.65,132.79,119.76,113.20,66.77,341.45；MS(ESI-):215.48。
2. preparation of 3, 4-dihydroxyphenylethanol
Figure BDA0002834613070000061
Respectively adding 75g (0.3456mol) of 3-bromo-4-hydroxyphenylethanol, 1500mL of water, 69g (1.725mol) of sodium hydroxide and 6.08g (17.28mmol) of 8-hydroxyquinoline copper into a three-necked bottle, heating to 95 ℃, and reacting for 5 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is finished, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 1, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into water phase, extracting by using tetrahydrofuran, adding product into organic phase, drying by anhydrous sodium sulfate, concentrating organic phase, distilling out 45g (0.2919mol) of hydroxytyrosol by a molecular evaporator under reduced pressure, wherein the molar yield is 84.46%, the total yield of two steps is 77.29%, and the HPLC purity is 99.28%.
Characterization data:
1HNMR(400MHz,MeOD):δ6.68-6.72(q,2H),6.53-6.55(d,1H),5.25(s,3H),3.68-3.71(t,2H),2.66-2.69(t,2H)；13CNMR(400MHz,MeOD):148.63,147.11,134.42,123.96,119.74,118.99,67.20,42.16；MS(ESI-):153.06。
example 2
1. Preparation of 3-bromo-4-hydroxyphenylethanol
1mol of 4-hydroxyphenylethanol, 1000mL of water and 400mL of acetone are added into a three-necked flask. And (3) putting the mixture into an ice water bath, cooling the mixture to below 5 ℃, and adding 2mol of potassium monopersulfate composite salt in batches. Slowly dripping prepared 50 wt% potassium bromide water solution (containing 2mol of potassium bromide) at the temperature below 5 ℃. After the addition was complete, the reaction was continued for an additional 2 hours in an ice-water bath. TLC analysis (developing agent PE: EA is 2: 1), after the reaction is finished, slowly adding 0.8mol of sodium thiosulfate in batches under ice water bath to quench the reaction, after the dropwise addition is finished, pouring the reaction solution into a single-mouth bottle, evaporating acetone under reduced pressure at the temperature of below 45 ℃, separating out crystals, performing suction filtration, washing with water, and drying by an air-blast drying oven to obtain 0.9012mol of product with the molar yield of 90.12%.
2. Preparation of 3, 4-dihydroxyphenylethanol
Respectively adding 0.8mol of 3-bromo-4-hydroxyphenylethanol, 4000mL of water, 2.5mol of potassium hydroxide and 0.04mol of 8-hydroxyquinoline copper into a three-necked bottle, heating to 100 ℃, and reacting for 6 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is completed, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 2, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into water phase, extracting by using butanol, adding product into organic phase, drying by anhydrous sodium sulfate, concentrating organic phase, and distilling out hydroxytyrosol by using molecular evaporator under reduced pressure, wherein the molar yield is 86.52%, and the HPLC purity is 99.15%.
Example 3
1. Preparation of 3-bromo-4-hydroxyphenylethanol
1mol of 4-hydroxyphenylethanol, 1000mL of water and 500mL of acetone are added into a three-necked flask. And (3) putting the mixture into an ice water bath, cooling the mixture to below 10 ℃, and adding 1mol of potassium monopersulfate composite salt in batches. Slowly dropwise adding a prepared 50 wt% sodium bromide aqueous solution (containing 3mol of sodium bromide) at a temperature below 10 ℃. After the addition was complete, the reaction was continued for another 3 hours in an ice-water bath. TLC analysis (developing agent PE: EA is 2: 1), after the reaction is finished, slowly adding 1mol of sodium bisulfite in batches in ice water bath to quench the reaction, after the dropwise addition is finished, pouring the reaction solution into a single-mouth bottle, evaporating acetone under reduced pressure below 45 ℃, separating out crystals, performing suction filtration, washing with water, and drying by an air-blast drying oven to obtain 0.8891mol of product with the molar yield of 88.91%.
2. Preparation of 3, 4-dihydroxyphenylethanol
Respectively adding 0.8mol of 3-bromo-4-hydroxyphenylethanol, 4000mL of water, 5mol of lithium hydroxide and 0.064mol of 8-hydroxyquinoline copper into a three-necked bottle, heating to 90 ℃, and reacting for 8 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is completed, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 1, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into water phase, extracting by using tert-butyl alcohol, adding product into organic phase, drying by anhydrous sodium sulfate, concentrating organic phase, distilling out hydroxytyrosol by using molecular evaporator under reduced pressure, wherein the molar yield is 83.63%, and the HPLC purity is 99.34%.
Example 4
Synthesis on a kilogram scale
1. Preparation of 3-bromo-4-hydroxyphenylethanol
400mol of 4-hydroxyphenylethanol, 300L of water and 100L of acetone are respectively added into a reaction kettle. And (3) putting the mixture into an ice water bath, cooling the mixture to below 5 ℃, and adding 200mol of potassium monopersulfate composite salt in batches. Slowly dropwise adding a prepared 50 wt% sodium bromide aqueous solution (containing 600mol of sodium bromide) at a temperature below 5 ℃. After the addition was complete, the reaction was continued for another 5 hours in an ice-water bath. TLC analysis (developing agent PE: EA is 2: 1), after the reaction is finished, slowly adding 300mol of sodium thiosulfate in batches under ice water bath to quench the reaction, after the dropwise addition is finished, pouring the reaction solution into a single-mouth bottle, evaporating acetone under reduced pressure below 45 ℃, separating out crystals, performing suction filtration, washing with water, and drying by an air-blast drying oven to obtain 346.8mol of product with the molar yield of 86.70%.
2. Preparation of 3, 4-dihydroxyphenylethanol
Respectively adding 300mol of 3-bromo-4-hydroxyphenylethanol, 1000L of water, 1500mol of sodium hydroxide and 9mol of 8-hydroxyquinoline copper into a reaction kettle, heating to 100 ℃, and reacting for 10 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is finished, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 1, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into water phase, extracting by using tetrahydrofuran, adding product into organic phase, drying by using anhydrous sodium sulfate, concentrating the organic phase, and distilling out hydroxytyrosol 249mol by using a molecular evaporator under reduced pressure, wherein the molar yield is 82.8%, and the HPLC purity is 99.01%.
The reaction scale is enlarged to a kilogram level, the purity of the product still reaches more than 99 percent, the yield is not obviously reduced, and the method is fully proved to be applicable to industrialized large-scale synthesis preparation.
Example 5
1. Preparation of 3-bromo-4-hydroxyphenylethanol
Same as in example 1
2. Preparation of 3, 4-dihydroxyphenylethanol
Respectively adding 0.35mol of 3-bromo-4-hydroxyphenylethanol, 1500mL of water, 1.8mol of sodium hydroxide and 17.5mmol of BFMO-cuprous iodide into a three-necked bottle, heating to 95 ℃, and reacting for 7 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is completed, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 1, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into water phase, extracting by using tetrahydrofuran, adding product into organic phase, drying by using anhydrous sodium sulfate, concentrating organic phase, and distilling out 188mmol of hydroxytyrosol by using molecular evaporator under reduced pressure, wherein the molar yield is 53.47% and the HPLC purity is 95.40%.
Example 6
1. Preparation of 3-bromo-4-hydroxyphenylethanol
Same as in example 1
2. Preparation of 3, 4-dihydroxyphenylethanol
Respectively adding 0.33mol of 3-bromo-4-hydroxyphenylethanol, 1500mL of water, 1.5mol of sodium hydroxide and 16.5mmol of copper acetylacetonate into a three-necked bottle, heating to 95 ℃, and reacting for 8 hours; after TLC analysis (developing agent PE: EA is 1: 1) reaction is completed, cooling to below 20 ℃, dropping 20 wt% hydrochloric acid, adjusting pH to 1, filtering insoluble solid by using kieselguhr after adjusting acid, extracting impurities from mother liquor by using dichloromethane, adding saturated common salt water into aqueous phase, extracting by using tetrahydrofuran, adding product into organic phase, drying by using anhydrous sodium sulfate, concentrating organic phase, and distilling under reduced pressure by using molecular evaporator to obtain hydroxytyrosol 198mmol, wherein the molar yield is 60.0%, and the HPLC purity is 92.72%.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A method of synthesizing hydroxytyrosol, which comprises the steps of b: reacting 3-bromo-4-hydroxyphenylethanol with an alkali metal hydroxide and a copper catalyst, wherein the copper catalyst is at least one of 8-hydroxyquinoline copper, copper acetylacetonate and BFMO-cuprous iodide,
Figure FDA0002834613060000011
2. the method of claim 1, wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or lithium hydroxide and the copper catalyst is copper 8-hydroxyquinoline.
3. The method of claim 2, wherein the molar ratio of 3-bromo-4-hydroxyphenylethanol to alkali metal hydroxide is from 1: 3-8, wherein the dosage of the copper catalyst is less than 10 mol% of the 3-bromo-4-hydroxyphenylethanol.
4. The method according to any one of claims 1 to 3, wherein the solvent in step b is water, and the reaction temperature is 80 to 110 ℃.
5. The method according to claim 4, wherein the step b is: dissolving 3-bromo-4-hydroxyphenylethanol, alkali metal hydroxide and a copper catalyst in a solvent, after the reaction is finished at the reaction temperature, cooling to the normal temperature, dropwise adding hydrochloric acid to adjust the pH to be below 2, filtering by using kieselguhr, adding saturated salt water into mother liquor, extracting by using an organic solvent, drying, concentrating the solvent, and distilling under reduced pressure by using a molecular evaporator to obtain a product.
6. The method according to claim 1, wherein step a is performed before step b: reacting 4-hydroxyphenylethanol with potassium monopersulfate composite salt and bromine salt to prepare 3-bromo-4-hydroxyphenylethanol,
Figure FDA0002834613060000012
7. the method of claim 6, wherein the bromine salt is sodium bromide or potassium bromide.
8. The method according to claim 7, wherein the molar ratio of the 4-hydroxyphenylethanol, the oxone complex salt and the bromine salt is 1: 0.5-3: 1 to 3.
9. The method according to any one of claims 6 to 8, wherein the solvent in step a is a mixed solvent of water and acetone, and the reaction temperature is below 25 ℃.
10. The method according to claim 9, wherein the step a is: dissolving 4-hydroxyphenylethanol in a solvent, adding potassium monopersulfate composite salt at a reaction temperature, then adding an aqueous solution of a bromine salt, adding a reducing agent after the reaction is finished to quench the reaction, decompressing and evaporating the solvent, filtering, washing and drying to obtain the product.
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